PCNSL is a rare extranodal aggressive lymphoma accounting for 4%- 6% of all extranodal lymphomas and 3%- 4% of brain tumors, with an overall low incidence rate. However, with the extension of life expectancy, the incidence of PCNSL has increased by 2-3 times in Western Europe and the United States over the past 20 years.
Conventional dose methotrexate (MTX) does not effectively cross the blood-brain barrier, and the treatment for newly diagnosed PCNSL is still based on high-dose methotrexate (HD-MTX) combined chemotherapy. In the early stages PCNSL, Batchelor et al. used an MTX dose of 8.0g/m², which could reach effective therapeutic concentrations in the cerebrospinal fluid (CSF). However, HD-MTX has significant nephrotoxicity, especially for elderly patients and those with renal insufficiency. In 2005, Khan et al. found that reducing the dose of MTX to 3.5g/m² could significantly reduce kidney toxicity. Although single-agent HD-MTX has some efficacy in treating PCNSL, the remission rate is still relatively low. High doses of cytarabine, dacarbazine, and thiotepa have a higher blood-brain barrier penetration rate, and these drugs combined with HD-MTX for treating PCNSL can further improve upon HD-MTX alone. The overall response rate (ORR) is approximately 60%-70%, the complete response (CR) rate is about 40%-50%, and the 5-year survival rate is around 30%. Neither the short-term efficacy nor the long-term survival is satisfactory.
Basic research has found that excessive activation of the BCR signaling pathway in PCNSL tumor tissue, and BTK inhibitors such as ibrutinib can effectively inhibit the BCR pathway to achieve therapeutic goals. A study used single agent ibrutinib to treat relapsed/refractory PCNSL, with an overall response rate (ORR) of 50%. Grommes et al. reported that ibrutinib combined with high-dose methotrexate (HD-MTX) with or without rituximab showed specific efficacy in treating relapsed/refractory PCNSL, with an ORR of 89% and a complete response (CR) rate of 67%. The efficacy was significantly higher than that of single-agent ibrutinib in treating relapsed/refractory PCNSL.
Based on these studies, we hypothesize that first-line treatment with BTK inhibitors combined with HD-MTX-based chemotherapy may further improve the efficacy of newly diagnosed PCNSL and prolong the duration of remission.However, as a first-generation BTK inhibitor, ibrutinib has a relatively high off-target effect, leading to increased drug resistance and adverse reaction rates. Zanubrutinib, as a new generation of BTK inhibitors, has shown more potent antitumor activity and lower adverse reactions than ibrutinib in head-to-head clinical studies. Previously, we conducted a phase II clinical study of ibrutinib combined with methotrexate and temozolomide in PCNSL, which showed that ibrutinib significantly improved patients' overall response rate and complete response rate. However, the duration of remission was relatively short. Therefore, this study uses the new generation of zanubrutinib and thiotepa, which have intense penetration into the central nervous system, aiming to improve patients' remission duration further.
At the same time, based on previous studies and clinical experience, elderly and patients with renal insufficiency have poor tolerance to methotrexate, often experiencing delayed MTX clearance and renal damage. The first four courses of this study removed methotrexate and only used the less toxic zanubrutiniba and thiotepa, providing a reference for future methotrexate-free treatment options.
